Aging and Western Diet Synergistically Impair Hepatic Thyroid Hormone Signaling to Promote Metabolic Dysfunction‐Associated Steatotic Liver Disease ( MASLD ) in Mice

ABSTRACT

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is primarily driven by a Western‐style diet and exacerbated with aging, yet underlying mechanisms remain unclear. Given the essential role of thyroid hormone (TH) in MASLD progression, we hypothesized that impaired intrahepatic TH action during aging promotes MASLD progression and severity of MASH with fibrosis. We evaluated hepatic TH metabolism in young (18–24 weeks) and old (108–120 weeks) C57BL/6J mice fed either a normal chow diet (NCD) or a Western diet with fructose (WDF) for 8 weeks. Liver histology, metabolic parameters, inflammatory and fibrotic markers, intrahepatic thyroxine (T4) and triiodothyronine (T3) concentrations, and activities of deiodinase enzymes (Dio1 and Dio3) were measured. Additionally, an in vitro hepatocyte senescence model using AML12 cells was employed to assess age‐related alterations in deiodinase expression and the therapeutic efficacy of resmetirom (an FDA‐approved thyromimetic). Aging and WDF synergistically exacerbated hepatic inflammation and fibrosis, accompanied by significant reductions in intrahepatic T4 and T3. Aging markedly decreased Dio1 activity, which converts T4 to active T3, whereas WDF partially restored Dio1 in old mice. Conversely, Dio3 activity, responsible for TH inactivation, increased with age but exhibited age‐dependent differential responses to WDF, findings mirrored in senescent hepatocytes. Notably, resmetirom significantly reduced senescence markers, inhibited senescence‐associated secretory phenotype (SASP) genes, inflammasome activation, endoplasmic reticulum (ER) stress, and activated autophagy. Collectively, our findings demonstrate that aging and stress by a Western‐style diet synergistically impair hepatic TH signaling, accelerating MASLD progression. Furthermore, resmetirom improved hepatic senescence, highlighting its potential therapeutic repurposing for aging‐associated hepatic pathologies, including MASLD.